Mast cells are major effector cells for immediate hypersensitivity and allergic diseases. In these settings, mast cell activation by IgE antibody and antigen contributes to pathology, such as in anaphylaxis, asthma, hay fever and atopic dermatitis or eczema. Activation of mast cells by other mechanisms is also thought to contribute to many other diseases, including certain autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. In host defense against pathogens, including some parasites and bacteria, mast cell activation can contribute to health by promoting clearance of the pathogen.
In allergic diseases, cross-linking of IgE bound to its high-affinity receptor, FcεRI, with multivalent antigen initiates the activation of mast cells by promoting the aggregation of FcεRI. This FcεRI-dependent activation results in degranulation (secretion of preformed mediators that are stored in the cytoplasmic granules, such as histamine, the synthesis and release of lipid mediators, including prostaglandin D2 (PGD2) and leukotriene C4 (LTC4), the de novo synthesis of proinflammatory lipid mediators, and the synthesis and secretion of cytokines and chemokines. In addition to these IgE/antigen-induced activation events, IgE binding to FcεRI in the absence of a specific antigen induces the up-regulation of FcεRI surface expression in mast cells and basophils and the prolonged survival of mouse mast cells under growth factor-limiting conditions. In mast cells, the activation of Ras-mediated protein kinase cascades is required for the expression of optimal immunologically-specific function when cell activation is initiated by antigen- and IgE-dependent aggregation of FcεRI.
Knowledge of the signaling pathways that result in the FcεRI-dependent secretion of mast cell mediators is increasing. In mast cells and basophils, the FcεRI receptor is a tetrameric complex comprised of a single 45 kDa α chain, which binds the Fc portion of IgE, a single 30 kDa β chain, and a homodimer of two 10 kDa γ chains. Aggregation of FcεRI activates Lyn, a Src family protein-tyrosine kinase that is constitutively associated with the β subunit. Activated Lyn then phosphorylates the immunoreceptor tyrosine-based activation motifs (ITAMs) of the β and γ subunits, inducing the recruitment and activation of Syk, which phosphorylates multiple substrates, including linker for activation of T cells (LAT) and phospholipase C-γ (PLC-γ). This results in the activation of two downstream cascades: the PLC-γ/protein kinase C cascade, required for degranulation and the release of mediators stored in the cells' cytoplasmic granules, and the Ras/ERK/phospholipase A2 cascade, critical for the release of cytokines and arachidonic acid.
Ras proteins are small GTPases important in the control of cell activation, proliferation and differentiation in diverse cell types. The mechanism by which Ras regulates such processes, through interactions with other intracellular molecules, is quite complex. Ras proteins are membrane-associated proteins that cycle between an active GTP-bound form and an inactive GDP-bound form. Conversion of the inactive GDP-bound Ras to the active GTP-bound state, e.g., when Ras guanine nucleotide exchange factors (GEFs) are recruited to the plasma membrane in response to an appropriate extracellular signal, relays responses initiated at the cell surface to multiple downstream signaling cascades. Ras can bind directly to the key effector Raf-1 to initiate activation of the ERK mitogen-activated protein (MAP) kinase cascade. However, Ras regulates a wide spectrum of cellular responses, and multiple effectors are required to mediate the many potential biological actions of Ras. Indeed, a diverse group of structurally and functionally distinct candidate Ras effectors in addition to Raf-1 have been identified, including GEFs for Ral, Ras GTPase-activating proteins (GAPs) such as p120 GAP and neurofibromin (NF1), MEKK1, AF6, phosphatidylinositol-3-kinase (Pl3K), RIN1.
Many different receptors expressed on the surface of diverse cell types can result in the activation of signal transduction pathways that are importantly influenced by Ras, and these pathways in turn determine whether, and to what extent, these cells respond to such cell surface receptor-dependent activation by proliferating, differentiating (i.e., developing new functional characteristics), and/or expressing specific functions. Depending on the circumstances, these “down-stream” consequences of the activation of Ras-dependent signal transduction pathways can have either adaptive (physiological) or maladaptive (pathological) consequences. Appropriate Ras-dependent mast cell secretion of histamine, serotonin, cytokines and other mediators can be important for host defense against parasites and other pathogens, whereas the inappropriate activation of these same pathways, for example, by a reaction to a bee-sting in patients who are allergic to components of bee venom, can lead to fatal anaphylaxis. Thus, Ras also represents an important element of signaling pathways that regulate the development and/or function of many cell types besides mast cells, including T cells, B cells, epithelial cells and nerve cells. (Ras represents a major regulator of many of the most fundamental biological processes involved in both health and disease.